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Molecular Breast Imaging: A Comprehensive Review
Molecular Breast Imaging: A Comprehensive Review Ashley I. Huppe, MD, Anita K. Mehta, MD, and Rachel F. Brem, MD, FACR, FSBI Molecular breast imaging (MBI), also called breast-specific gamma imaging (BSGI), has been an integral component of our breast imaging practice for over a decade. Unlike mammography and ultrasound that are based on anatomy, MBI is a physiologic approach to breast cancer detection. MBI detects additional foci of occult breast cancer in 9.0% of women with newly diagnosed breast cancer, has a high sensitivity for detecting high-risk lesions, and detects 98% of invasive breast cancer and 91.0% of ductal carcinoma in situ. Furthermore, in surveillance of high-risk women, BSGI/MBI detects occult cancer in up to 16.5 per 1000 women. This modality is increasingly being used to assess response to treatment in women undergoing neo-adjuvant chemotherapy and for adjunct screening in women with dense breasts. It has been shown to influence surgical management in nearly a quarter of women with newly diagnosed breast cancer. The Society of Nuclear Imaging has established clinical indications and The American College of Radiology has established appropriateness criteria as well as an accreditation program for MBI. A BIRADS-like lexicon for MBI has also been described. Initially, MBI utilized 10-20 mCi of 99 mTc sestamibi, however, recent studies have reported the use of 5-10 mCi with equal sensitivity to the higher dose of radiotracer. There are over 300 studies in the literature about MBI/BSGI with increasing integration of MBI into clinical practice. This chapter will describe the history, current literature and indications, clinical use, approach to biopsy and integration of MBI into clinical practice. Semin Ultrasound CT MRI ]:]]]-]]] C 2017 Elsevier Inc. All rights reserved.
History and Current Use
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reast cancer-related mortality, currently the second leading cause of cancer death in the United States,1 has declined over the last 30 years by over 30%,2 in large part due to mammographic screening. Although breast cancer mortality has decreased, mammography, which relies on the anatomic differences between cancer and normal breast parenchyma, remains an imperfect examination. The overall sensitivity of screening mammography is 75%-85%. However, in women with dense breast tissue, the sensitivity is significantly reduced to 42%-68%.3-5 Furthermore, dense breast tissue is an independent risk factor for the development of breast cancer.6 Ultrasound, the second most common modality in breast imaging, also utilizes an anatomic approach to finding breast
George Washington University, Comprehensive Breast Care Center, Washington, DC. Address reprint requests to Ashley I. Huppe, MD, George Washington University, Comprehensive Breast Care Center, 2300 M Street NW, 8th Floor, Washington, DC 20037. E-mail: [email protected]
http://dx.doi.org/10.1053/j.sult.2017.10.001 0887-2171/& 2017 Elsevier Inc. All rights reserved.
cancer. It too has limitations, including a high false positive rate. Adjunct imaging modalities are now available that rely on physiologic and not purely anatomic findings to improve breast cancer detection. Molecular breast imaging (MBI), also referred to as breastspecific gamma imaging (BSGI), is a modality that utilizes dedicated gamma cameras and an injected radiopharmaceutical to identify breast cancer. In MBI, the radiotracer uptake is proportional to blood flow and mitochondrial activity as well as other physiologic factors, resulting in preferential uptake by cancer cells. The Food and Drug Administration initially approved the use of technetium-99m sestamibi for scintimammography in 1997, and although a conventional gamma camera was employed to image the breast at that time, the technology demonstrated good sensitivity and specificity for tumors larger than 15 mm.7,8 However, the inability to reliably image subcentimeter cancer and to directly compare to mammography markedly limited the integration of scintimammography into clinical practice. With the development of compact, high-resolution breast-specific gamma camera systems, the limitations of conventional gamma cameras were 1
2 resolved, and MBI can now reliably image subcentimeter cancers9 as well as image in projections comparable to mammography, resulting in the meaningful integration of MBI into clinical practice. There are several different configurations of breast-specific gamma cameras, including single-headed and dual-headed gamma cameras.10 Currently, the commercially available detectors use sodium iodide crystals or a cadmium zinc telluride (CZT) semiconductor. In the research environment, the parameters of the different types of detectors vary.10 However, numerous studies confirm that both types of detectors reliably image subcentimeter cancers and have comparable sensitivity and specificity.9,11-13 The ability to detect subcentimeter cancers is not impacted by whether a single- or dual-headed camera is used, however, with a dualheaded camera, the time for image acquisition may be shorter and the cost of the equipment may substantially increase. Another difference between a single- and dual-headed camera is that with a second detector, positioning may become more difficult due to the inability to visualize the breast during positioning.14 MBI is performed by injecting the radiopharmaceutial technetium-99m sestimibi, called Miraluma when used for breast imaging, into the venous system. In a patient with known breast cancer, the injection should be performed in the contralateral arm to avoid lymphatic uptake from extravasation of the radioisoptope during injection, as this will be imaged as axillary uptake and can be mistaken for lymphatic involvement.15 The patient is positioned while seated with the breast gently compressed between the gamma detector and compression plate or the 2 gamma detectors in a dual-headed camera. Bilateral conventional craniocaudal and mediolateral oblique views are obtained that allow for direct correlation with mammography. For the Dilon Camera, the detector is on an articulating arm that can be rotated to obtain addition projections. With the Gamma Medica and GE Cameras, the detectors are on a gantry, similar to a mammography unit and additional images can be obtained by angling the gantry. The radiologist, in a manner comparable to diagnostic mammography, reviews the initial images. Additional images can be acquired as deemed necessary and may include exaggerated craniocaudal, true lateral, or in the case of a single detector camera, imaging with the detector on the opposite side of the breast. No additional radiotracer is administered when additional images are obtained. Imaging in projections comparable to mammography allows for multimodality correlative imaging. “Second-look” mammography is frequently utilized to identify MBI-detected lesions with subtle mammographic findings that might not have been appreciated before the MBI findings (Fig. 1). A complete MBI study consists of 4-12 images (significantly fewer than MRI), which allows for rapid interpretation and efficient workflow. In our experience, the time for interpretation of MBI is far less than that of MRI. With the current emphasis on workflow and efficiency, the markedly fewer images and shorter interpretation time allows for efficient as well as effective integration into clinical practice.
A.I. Huppe et al. While MRI is commonly utilized in many clinical scenarios, we find that approximately 15% of patients are unable to undergo evaluation by MRI due to implantable devices/ metallic foreign bodies, body habitus, renal insufficiency, patient positioning, and claustrophobia. Reticence to undergo MRI is a significant issue with the ACRIN 6666 trial demonstrating that 48% of women at substantially increased risk of breast cancer refused MRI, even when it was offered at no cost.16,17 Additional concerns with MRI include gadolinium accumulation in the brain, particularly with repeated studies. In our practice, it is critical to have MBI to offer to women who cannot or will not undergo MRI as an alternative physiologic imaging modality to detect cancers that are not visible with mammography or ultrasound. MBI has a high sensitivity, comparable to that of MRI, of 89%-96.4% (97% for invasive cancers and 93.8% for ductal carcinoma in situ [DCIS]).18-20 Of note, the sensitivity of MBI is independent of breast density, with sensitivities of 95.1% in dense breasts and 95.8% in nondense breasts.22,22 Not only can MBI detect cancer, but MBI can also detect high-risk lesions such as ADH and ALH.23 This can be of clinical importance especially as the risk of developing breast cancer in young women with ADH and in women with multiple foci of ADH has recently been shown to be as high as 50%.24 In this high-risk population, risk reduction strategies are often considered and may include chemoprevention. Therefore, the identification of ADH and other high-risk lesions is clinically important. MBI has many advantages, however, as with all imaging modalities, there are disadvantages. The disadvantages of MBI include the lack of anatomy included when compared to MRI and the radiation required for MBI. Initially, MBI was performed using 20-30 mCi (740-1100 megabecquerels [MBq]) of technetium sestamibi. Recently, a number of studies have demonstrated the use of 5-10 mCi, a 2.5-fold reduction in injected dose, with maintenance of sensitivity and specificity.19,20,25 The ability to utilize lower dose radiotracer has been demonstrated with both NaI detectors19 and CZI detectors.25 While both mammography and MBI incur radiation, the former involves exposure to the breast, while MBI is associated with whole-body radiation. A MBI examination using 8 mCi of technetium sestamibi has an estimated dose to the breast of 0.07 mGy/mCi,26 or approximately 0.53 mGy. However, the effective whole-body dose of MBI is approximately 0.325 mSv/ mCi, or 2.5 mSv for an administered activity of 8 mCi.26 In comparison, the effective dose from 2-view digital mammography is 0.5 mSv. Although the use of MBI for generalized screening is not recommended, its use for diagnostic evaluation, in patients with contraindications to MRI, in women with newly diagnosed breast cancer and in women with dense breast tissue is reasonable.27 It is important to note that the MBI dose is significantly lower than the annual exposure limit of 50 mSv set by the U.S. federal government for radiation workers, and comparable to that of other cancer screening modalities. The purpose of this chapter is to provide a comprehensive review of MBI to include current indications and limitations, imaging technique, diagnostic performance of MBI including
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Figure 1 (A) MBI performed in this patient with a known malignancy in the contralateral breast demonstrates a focus of abnormal uptake in the central right breast. (B) “Second-look mammography” demonstrates a corresponding asymmetry seen when the nipple is in profile. Stereotactic biopsy of the asymmetry yielded atypical ductal hyperplasia, which was upgraded to DCIS upon excision.
up-to-date research, comparison with other imaging modalities and technical aspects regarding implementation of MBI into a practice.
Clinical Use MBI has been used in clinical practice for over 15 years with over 300 manuscripts describing the clinical and technical aspects of the technology. The sensitivity of MBI ranges from 89%-96%18-20 comparable to MRI.28 Several studies have compared MBI and MRI and have found comparable sensitivity with higher specificity for MBI.29 Since the indications for MBI are similar to MRI, it is of note that the sensitivity of the 2 modalities are similar, with a possibly higher specificity for MBI.9 As the clinical indications for MBI are in large part comparable to those of MRI, it can be integrated into clinical practice in a similar fashion. Indications for MBI include evaluation for extent of disease or occult disease in women
with a known diagnosis of cancer, high-risk surveillance, equivocal mammographic/sonographic findings, clinically challenging situations such as direct silicone implants and response to neo-adjuvant chemotherapy (Fig. 2). Studies have demonstrated that MBI detects occult foci of cancer in approximately 9%-11% of women with newly diagnosed breast cancer,30,31 changes surgical management in about a quarter of women with newly diagnosed breast cancer,32 and has similar sensitivity to and possibly higher specificity than MRI in comparable clinical situations.9 In addition, MBI has the potential to overcome the limitations of mammography when evaluating for local tumor recurrence.33 While mammography is the first-line modality for monitoring women following breast conservation therapy, it can be limited by morphologic changes in the posttreatment breast. Although the data is currently preliminary, studies have indicated that MBI is not adversely affected by posttherapeutic changes of the breast, and is a suitable alternative to MRI in this setting.34,35 A notable indication for MBI is problem solving for indeterminate cases or challenging clinical situations including
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Figure 2 (A) MBI in a patient with a known cancer demonstrates large mass-like uptake in the left breast. (B) Follow-up MBI after neo-adjuvant chemotherapy demonstrates complete resolution of uptake in the left breast, consistent with favorable response.
cases that require additional evaluation following a complete mammographic and sonographic evaluation. Additionally, certain clinical situations, such as women with implants or direct silicone injections for augmentation, present a diagnostic challenge when imaged with mammography, ultrasound, and even MRI (Fig. 3). Finally, MBI can also be used in evaluation for primary breast cancer in women with metastases or metastatic axillary lymphadenopathy of unknown primary. While MRI is often used for the detection of occult malignancy, given the similar sensitivities for cancer detection, MBI is an important alternative when MRI is not an option. In women with newly diagnosed breast cancer, MBI detects additional foci of disease comparable to that reported for MRI. In one series, MBI demonstrated occult disease in the ipsilateral breast in 6% of women and in the contralateral breast in an additional 3% with a PPV of positive MBI findings of 35%.30 In a second series of 138 women with newly diagnosed breast cancer additional foci of disease were detected in 11% of women with a PPV of 60% for suspicious findings on MBI.31 In this population of women where detection of additional disease is critical and where the specificity is lower, the availability of direct gamma-guided biopsy is critical. In 218 women with newly diagnosed breast cancer thought to be
eligible for breast conserving therapy, MBI resulted in a change in management in 26% of patients.32 In this study, pathology of the mastectomy specimen confirmed that all of the women who were converted from breast conserving therapy to mastectomy due to MBI findings would have had residual disease had breast cancer therapy been performed. Studies evaluating the impact of pathologic subtypes of breast cancer on MBI sensitivity have demonstrated that both tumor size, grade, and pathologic subtype are important. In a series of 149 invasive breast cancers, the sensitivity of MBI was 98%. The cancers were stratified by size and pathologic grade. All invasive cancers measuring greater than 7 mm and all cancers grade 2 or 3, regardless of size (even those less than 5 mm) were positive. Of the grade 1 invasive cancers less than 7 mm, 50% were positive, demonstrating that MBI can detect virtually all clinically significant breast cancer and that grade and size are both factors in MBI detection of cancer.11 Invasive lobular carcinoma is often difficult to detect clinically as well as with traditional imaging with mammography and ultrasound. In a multi-institutional study, the sensitivity of MBI for detecting invasive lobular carcinoma was greater than mammography, ultrasound, or MRI.36 In this study, the sensitivity of MBI was 93% compared to MRI with a sensitivity of 83% for
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Figure 3 (A) Screening mammogram in a patient with a history of silicone injections demonstrates innumerable injection granulomas significantly limiting evaluation for malignancy. (B) MBI in this patient demonstrates no abnormal uptake. (Color version of figure is available online.)
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6 invasive lobular cancer. Similar findings were reported for the sensitivity of ILC in a series reporting the sensitivity of MBI by pathology subtype.37 Several studies have shown that MBI cannot reliably assess axillary involvement of breast cancer, although axillary uptake due to extravasation at the time of radiotracer injection is higher than in metastatic lymphadenopathy.38 Over 30 states now have density inform laws requiring women be told their breast density and some require information about adjunct imaging modalities available to detect mammographically occult cancers. The sensitivity of MBI is equal in women with dense and nondense breasts.21 Yet, the approach to supplemental screening in women with dense breasts varies. Ultrasound remains the primary modality for supplemental screening in women with dense breasts.39 Several recent studies have reported the use of MBI for supplemental screening in women with dense breasts. The rationale is that the cancer detection rate of 7-16 cancers per thousand women screened with MBI is substantially higher than the 2-7 cancers found with ultrasound.22,40 Screening with MBI also has lower recall rate of 6%-8% and a higher PPV3 of 33%.25 The issue of the additional radiation with MBI must be considered. Nevertheless, MBI is increasingly being used for adjunct screening in women with dense breast due to the more widespread use of lower dose of the radioisotope and the substantially higher cancer detection rate. Furthermore, screening with MBI results in an entire study consisting of 8 images, far fewer than the hundreds or thousands of images obtained with tomosynthesis, handheld or automated screening ultrasound, or MRI. MRI is indicated to screen women at greater than 20% lifetime risk of breast cancer.41 Studies have shown that in women at increased risk of breast cancer who cannot or will not undergo MRI can expect a similar rate of cancer detection using MBI42,43 (Fig. 4). In a comparative study of MRI and MBI in women at increased risk for breast cancer with dense breast tissue, the sensitivities of MRI and MBI were comparable, and the specificity of MBI was higher.29 Of note, the majority of incremental cancers detected with MBI screening are invasive cancers. Furthermore, in a study comparing the costs of screening, diagnostic work-up and biopsies, the cost per cancer detected with mammography and MBI was lower than mammography alone.44 Several studies have evaluated the use of MBI in evaluating both the presence and the extent of residual tumor in women undergoing neoadjuvant chemotherapy. In one study of 122 patients where MBI was compared to MRI, the assessment of residual tumor was equal in MBI and MRI. However, when assessment of extent of residual tumor was compared, both MRI and MBI underestimated the extent of residual tumor in luminal-type breast cancer, while MRI underestimated the extent of residual disease more than MBI in Her2 positive breast cancer. Both MBI and MRI generated accurate tumor sizes and extent of residual disease in triple negative breast cancer.45 A meta-analysis of 3 studies, which included 107 patients, evaluating MBI during neo-adjuvant chemotherapy reported a sensitivity of 87% and a specificity of 93%.46 Larger, multi-institutional studies are needed to further evaluate the
role of MBI in assessing the presence and extent of residual disease following neo-adjuvant chemotherapy. A negative MBI examination is clinically important. In the screening environment, whether it be in women with dense breasts or in high-risk women, the 98% negative predictive value is extremely reassuring.43 In women with newly diagnosed breast cancer, confirming only the known cancer with no other areas of abnormality is critically important in management decisions.
Imaging Technique MBI examinations are performed following an intravenous injection of technetium-99m sestamibi. No patient preparation is necessary. Some have suggested fasting for several hours before the examination and keeping the patient warm.22 However, we have not found that necessary. Tc-99m sestamibi, a radiopharmaceutical with a 140 Kev emitting gamma ray, was initially approved as a myocardial perfusion agent in 1991 and has since had a history of safe use with minimal adverse events; the only absolute contraindications are pregnancy and allergy to the radiotracer. The reported incidence of adverse effects is low (1-6 per 100,000). Although the initial dose of Tc-99m sestamibi was 20-30 mCi, we and others are using 5-10 mCi.19,25 Imaging begins immediately after radiotracer administration and continues for 175,000 counts which takes 5-10 minutes per image. The radiotracer is taken up by the breast almost immediately following injection, and the activity remains relatively constant for the duration of the study. A nuclear medicine technologist with training in breast imaging should perform the imaging or, alternatively, a nuclear medicine technologist can perform the injection with the imaging performed by a mammography technologist. Highresolution images are obtained while the breast is in gentle compression using conventional craniocaudal and mediolateral oblique mammographic positioning with careful attention to inclusion of the entirety of the breast. Similar to mammography, additional views can be obtained to completely evaluate the breast such as exaggerated craniocaudal, true lateral, and axillary tail views. The examination is performed with the patient comfortably seated and requires approximately 40-50 minutes. Patients undergoing MBI can listen to music or watch videos during the examination. Similar to MRI, when MBI is performed for surveillance in high-risk women or for follow-up of a previously visualized finding, it is optimal to perform the study during the follicular phase of the menstrual cycle, that is, days 7-14. This approach should minimize the background parenchymal radiotracer uptake, similar to background parenchymal enhancement with MRI. However, if there is a clinical indication, the examination can and should be performed anytime during the menstrual cycle. In women with newly diagnosed breast cancer, it is recommended that the injection be in the contralateral arm to avoid uptake in the axilla from extravasation and confound interpretation of axillary involvement.38 Radiologists experienced in breast imaging should perform interpretation of MBI examinations. As with most breast
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Figure 4 Screening mammogram in a high-risk patient demonstrates heterogeneously dense breast tissue. The parenchymal pattern was stable without mammographic evidence for malignancy. Subsequent imaging with MBI in this patient demonstrates mass-like uptake in the lower outer quadrant that yielded invasive lobular carcinoma upon tissue sampling.
imaging, multimodality correlation results in optimal interpretation. This may include “second-look mammography” where, based on MBI findings, the mammogram is reevaluated and subtle findings previously thought to be insignificant are now re-considered. Furthermore, in a study evaluating 173 cases of positive screening MBI examinations, correlation with clinical history or other imaging modalities resulted in confirmation of correlative benign findings in 31% of the cases.44 Interpretation of a positive MBI examination, whether performed for screening or diagnostic reasons, often
leads to directed ultrasound to identify the abnormality for biopsy (Fig. 5). Since the widespread use of breast MRI, breast imaging radiologists have become adept at correlating ultrasound findings with MRI, and can translate this ability to MBIidentified findings. In a study of 1585 women who underwent screening MBI, 3% went on to biopsy. Of those, 74% has the MBI-detected lesions recommended for biopsy were identified with directed ultrasound and 26% required MRI to target the suspect lesion.44 The use of MRI can be obviated by the availability of direct gamma-guided biopsy. This demonstrates
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Figure 5 (A) Molecular breast imaging in this patient with known right breast cancer demonstrates an abnormal focus of uptake in the medial left breast for which second-look ultrasound was recommended. (B) Second-look ultrasound demonstrates an irregularly shaped hypoechoic mass corresponding to the MBI finding. Biopsy yielded invasive ductal carcinoma. (Color version of figure is available online.)
that although the majority of lesions identified with MBI can be seen with directed ultrasound, direct gamma-guided biopsy is needed to optimally integrate MBI into clinical practice. A direct gamma-guided biopsy device for MBI-identified lesions has been FDA cleared for the Dilon Technologies camera (GammaLoc, Dilon Technologies) since 2009 and the GE Camera (GE, Discovery NM 750b) biopsy device recently received FDA clearance. With the availability of a direct gamma-guided biopsy device, optimal integration of MBI into clinical practice is possible. In a recent study of 104 gammaguided biopsies, all of which were successfully performed, 9 invasive cancers, 6 DCIS, and 17 high-risk lesions were found demonstrating a PPV of 30.8% for abnormal pathology
and 16.3% for cancer.47 These findings are similar to that reported for MRI-guided biopsy.48 A lexicon has been developed for MBI in order to improve and standardize MBI imaging reports.49 Components of the lexicon are similar to BIRADS whereby the technique, background enhancement, technical factors, and standardized lesion terminology are included. This has been shown to improve interobserver variability and accuracy. However, there are notable differences between BIRADS and the MBI lexicon in that BIRADS 3, probably benign, lesions identified with MBI imaging had a malignancy rate of 5%50 compared with the accepted 2% for mammography.51
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Implementation Into Practice MBI has become an integral component of our breast imaging practice. Without it, a substantial percentage of patients do not have the ability to obtain critically important physiologic imaging. MBI is not meant to replace other breast imaging modalities. Rather, it is an addition to our armamentarium of technology and modalities to allow for the diagnosis of early, curable breast cancer. It will not replace screening mammography, but as discussed above, contributes to the diagnosis of cancer in numerous clinical situations and in screening in women at increased risk and with dense breast tissue. Successful integration in a clinical practice requires that MBI be in the breast imaging area. When MBI is placed in nuclear medicine, the fragmentation from breast imaging makes it nearly impossible to seamlessly integrate into clinical practice. For some MBI imaging systems, such as the Dilon system, a dedicated room is not necessary since the device is approximately the size of an ultrasound unit and is portable. For others, which use a fixed gantry such as the Gamma Medica and GE systems, a dedicated room is necessary. There is no additional shielding that is needed for the room where the injections or the imaging occurs. Any facility using MBI must have access to a physicist who maintains a radioactive materials license, an appropriately licensed physician, a state-licensed nuclear technician for radiotracer injection and a radiation safety officer. For many tertiary care centers, these individuals are generally readily available, often already integrated into the radiology department. However, this may present more of a challenge for smaller, community-based practices with more limited resources. Several of the camera system vendors have a program for turn-key integration of nuclear medicine imaging of the breast in order to make integration of MBI into clinical practice easier. Practices must additionally consider the coverage by insurance and acceptance by referring clinicians, both of which will vary among communities. As with any new technology, familiarity by the referring physicians is critical for success. Presenting MBI at hospitalbased conferences can be extremely helpful as can identifying specific indications where MBI is advantageous. The Society of Nuclear Medicine has published clinical indications for MBI52 and the American College of Radiology has published appropriateness criteria for MBI. There is also an accreditation program by the ACR for MBI.53,54 More recently, the ACR has developed a teaching module for MBI interpretation with a no-cost online program of over 100 cases with quizzes and self-assessment, which physicians incorporating MBI into their clinical practice should consider reviewing.
Conclusion MBI is a valuable tool for both breast cancer screening and evaluation of breast cancer. It provides a means of physiologic imaging for a significant subset of women for whom MRI is not an option, while demonstrating similar sensitivities and improved specificities over MRI. It is a clinically important option for women who cannot undergo MRI, or for screening
9 women with dense breasts. Future directions include the development a newer radiotracers and further development of breast-specific gamma cameras, particularly with integrated correlative imaging with mammography and possibly MRI. Additionally, rigorous, multi-institutional studies evaluating MBI as well as comparing MBI to MRI are necessary, as are further additional cost analysis studies to further our understanding of the optimal use of this exciting emerging technology.
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imaging, a molecular breast imaging technique. Am J Roentgenol 198(1): W69-W75, 2012 Kuhn KJ, Rapelyea JA, Torrente J, et al: Comparative diagnostic utility of low-dose breast-specific gamma imaging to current clinical standard. Breast J 22(2):180-188, 2016 Rhodes DJ, Hruska CB, Conners AL, et al: Journal club: molecular breast imaging at reduced radiation dose for supplemental screening in mammographically dense breasts. Am J Roentgenol 204(2):241-251, 2015 Rechtman LR, Lenihan MJ, Lieberman JH, et al: Breast-specific gamma imaging for the detection of breast cancer in dense versus nondense breasts. Am J Roentgenol 202:293-298, 2014 Hruska CB: Molecular breast imaging for screening in dense breasts: state of the art and future directions. Am J Roentgenol 208:275-283, 2017 Ling CM, Coffey CM, Rapelyea JA, et al: Breast-specific gamma imaging in the detection of atypical ductal hyperplasia and lobular neoplasia. Acad Radiol 19(6):661-666, 2012 Hartmann LC, Degnim AC, Santen RJ, et al: Atypical hyperplasia of the breast—risk assessment and management options. N Engl J Med 372:78-89, 2015 Hruska CB, Weinmann AL, Tello Skjerseth CM, et al: Proof of concept for low-dose molecular breast imaging with a dual-head CZT gamma camera. II. Evaluation in patients. Med Phys 39(6):3476-3483, 2012 Cardiolite Kit for the preparation of technetium Tc99m sestamibi for injection 513121-1007, 2008; Available at: http://www.accessdata.fda. gov/drugsatfda_docs/label/2008/019785s018lbl.pdf. Accessed September 16, 2017. Hendrick RE, Tredennick T: Benefit to radiation risk of breast-specific gamma imaging compared with mammography in screening asymptomatic women with dense breasts. Radiology 281(2):583-588, 2016 Houssami N, Ciatto S, Macaskill P, et al: Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. J Clin Oncol 26(19):3248-3258, 2008 Kim BS: Usefulness of breast-specific gamma imaging as an adjunct modality in breast cancer patients with dense breasts: a comparative study with MRI. Ann Nucl Med 26:131-137, 2012 Brem RF, Shahan C, Rapelyea JA, et al: Detection of occult foci of breast cancer using breast-specific gamma imaging in women with one mammographically or clinically suspicious breast lesion. Acad Radiol 17(6): 735-743, 2010 Zhou M, Johnson N, Gruner S, et al: Clinical utility of breast-specific gamma imaging for evaluation disease extent in the newly diagnosed breast cancer patient. Am J Surg 197(2):159-163, 2009 Edwards C, Williams S, McSwain AP, et al: Breast-specific gamma imaging influences surgical management in patients with breast cancer. Breast J 19 (5):512-519, 2013 Lu WL, Jansen L, Post WJ, et al: Impact on survival of early detection of isolated breast recurrences after the primary treatment for breast cancer: a meta-analysis. Breast Cancer Res Treat 114(3):403-412, 2009 Cwikla JB, Kolasinska AD, Buscombe JR, Hilson AJW: Cancer Biotherapy and Radiopharmaceuticals 15(4):367-372, 2009 Kolasinska AD, Buscombe JR, Cwikla JB, et al: The role of scintimammography and mammography in recurrent breast cancer. Evaluation of their accuracy using ROC curves. Nucl Med Rev Cent East Eur 4 (2):77-82, 2001 Brem RF, Ioffe M, Rapelyea JA, et al: Invasive lobular carcinoma detection with mammography, sonography, MRI and breast-specific gamma imaging. Am J Roentgenol 192(2):379-383, 2009
37. Connors AL, Jones KN, Hruska CB, et al: Direct-conversion molecular breast imaging of invasive breast cancer: imaging features, extent of invasive disease, and comparison between invasive ductal and lobular histology. Am J Roentgenol 205:W374-W381, 2015 38. Werner J, Rapelyea JA, Yost KG, Brem RF: Quantification of radio-tracer uptake in axillary lymph nodes using breast specific gamma imaging (BSGI): benign radio-tracer extravasation versus uptake secondary to breast cancer. Breast J 15:579-582, 2009 39. Brem RF, Tabar L, Duffy SW, et al: Assessing improvement in detection of breast cancer with three-dimensional automated breast US in women with dense breast tissue: the SomoInsight study. Radiology 274(3):663-673, 2015 40. Shermis RB, Redfern RE, Burns J, Kudrolli H: Molecular breast imaging in breast cancer screening and problem solving. Radiographics 37:1309-1327, 2017 41. Saslow D, Boetes C, Burke W, et al: American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin 57:75-89, 2007 42. Brem RF, Rapelyea JA, Zisman G, et al: Occult breast cancer: scintimammography with high-resolution breast-specific gamma camera in women at high risk for breast cancer. Radiology 237(1):274-280, 2005 43. Brem RF, Ruda RC, Yang JL, et al: Breast specific gamma imaging for the detection of mammographically occult breast cancer in women at increased risk. J Nucl Med 57(5):678-684, 2016 44. Hruska CB, Conners AL, Jones KN, et al: Diagnostic workup and costs of a single supplemental molecular breast imaging screen of mammographically dense breasts. Am J Roentgenol 204:1345-1353, 2015 45. Lee HA, Ko BS, Ahn SH, et al: Diagnostic performance of breast-specific gamma imaging in the assessment of residual tumor after neoadjuvant chemotherapy in breast cancer patients. Breast Cancer Res Treat 145:91-100, 2014 46. Collarino A, de Koster EJ, Valdes Olmos RA, et al: Is technetium-99m sestamibi imaging able to predict pathologic nonresponse to neo adjuvant chemotherapy in breast cancer? A meta-anaylsis evaluating current use and shortcomings. Clin Breast Cancer 2017 Jun 29. [Epub ahead of print] 47. Brem RF, Mehta AK, Rapelyea JA, et al: Gamma-guided minimally invasive breast biopsy: initial clinical experience. Am J Roentgenol 2017. http://doi.org/10.2214/AJR.17.18513, [in press] 48. Sedora Roman NI, Mehta TS, Sharpe RE, et al: Proposed biopsy benchmarks for MRI based on an audit of a large academic center. Breast J 2017. [Epub ahead of print] 49. Conners AL, Maxwell RW, Tortorelli CL, et al: Gamma camera breast imaging lexicon. Am J Roentgenol 199:W767-W774, 2012 50. Narayanan D, Madsen KS, Kalinyak JE, Berg WA: Interpretation of positron emission mammography: feature analysis and rates of malignancy. Am J Roentgenol 196:956-997, 2011 51. Sickles EA, D’Orsi CJ: Follow-up and outcome monitoring. In: ACR BIRADS Atlas, Breast Imaging Reporting and Data System. Reston, VA: American College of Radiology, 2013 52. Goldsmith SJ, Parsons W, Guiberteau MJ, et al: SNM practice guideline for breast scintigraphy with breast-specific gamma-cameras 1.0. J Nucl Med Technol 38:219-224, 2010 53. Getting Started. CR Nuclear Medicine & PET Accreditation, www. acraccreditation.org/Modalities/Nuclear-Medicine-and-PET. 54. American College of Radiology: Diagnostic Radiology: Nuclear Medicine Practice Parameters and Technical Standards—American College of Radiology. American College of Radiology 2017. www.acr.org/QualitySafety/Standards-Guidelines/Practice-Guidelines-by-Modality/ Nuclear-Medicine
History and Current Use
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reast cancer-related mortality, currently the second leading cause of cancer death in the United States,1 has declined over the last 30 years by over 30%,2 in large part due to mammographic screening. Although breast cancer mortality has decreased, mammography, which relies on the anatomic differences between cancer and normal breast parenchyma, remains an imperfect examination. The overall sensitivity of screening mammography is 75%-85%. However, in women with dense breast tissue, the sensitivity is significantly reduced to 42%-68%.3-5 Furthermore, dense breast tissue is an independent risk factor for the development of breast cancer.6 Ultrasound, the second most common modality in breast imaging, also utilizes an anatomic approach to finding breast
George Washington University, Comprehensive Breast Care Center, Washington, DC. Address reprint requests to Ashley I. Huppe, MD, George Washington University, Comprehensive Breast Care Center, 2300 M Street NW, 8th Floor, Washington, DC 20037. E-mail: [email protected]
http://dx.doi.org/10.1053/j.sult.2017.10.001 0887-2171/& 2017 Elsevier Inc. All rights reserved.
cancer. It too has limitations, including a high false positive rate. Adjunct imaging modalities are now available that rely on physiologic and not purely anatomic findings to improve breast cancer detection. Molecular breast imaging (MBI), also referred to as breastspecific gamma imaging (BSGI), is a modality that utilizes dedicated gamma cameras and an injected radiopharmaceutical to identify breast cancer. In MBI, the radiotracer uptake is proportional to blood flow and mitochondrial activity as well as other physiologic factors, resulting in preferential uptake by cancer cells. The Food and Drug Administration initially approved the use of technetium-99m sestamibi for scintimammography in 1997, and although a conventional gamma camera was employed to image the breast at that time, the technology demonstrated good sensitivity and specificity for tumors larger than 15 mm.7,8 However, the inability to reliably image subcentimeter cancer and to directly compare to mammography markedly limited the integration of scintimammography into clinical practice. With the development of compact, high-resolution breast-specific gamma camera systems, the limitations of conventional gamma cameras were 1
2 resolved, and MBI can now reliably image subcentimeter cancers9 as well as image in projections comparable to mammography, resulting in the meaningful integration of MBI into clinical practice. There are several different configurations of breast-specific gamma cameras, including single-headed and dual-headed gamma cameras.10 Currently, the commercially available detectors use sodium iodide crystals or a cadmium zinc telluride (CZT) semiconductor. In the research environment, the parameters of the different types of detectors vary.10 However, numerous studies confirm that both types of detectors reliably image subcentimeter cancers and have comparable sensitivity and specificity.9,11-13 The ability to detect subcentimeter cancers is not impacted by whether a single- or dual-headed camera is used, however, with a dualheaded camera, the time for image acquisition may be shorter and the cost of the equipment may substantially increase. Another difference between a single- and dual-headed camera is that with a second detector, positioning may become more difficult due to the inability to visualize the breast during positioning.14 MBI is performed by injecting the radiopharmaceutial technetium-99m sestimibi, called Miraluma when used for breast imaging, into the venous system. In a patient with known breast cancer, the injection should be performed in the contralateral arm to avoid lymphatic uptake from extravasation of the radioisoptope during injection, as this will be imaged as axillary uptake and can be mistaken for lymphatic involvement.15 The patient is positioned while seated with the breast gently compressed between the gamma detector and compression plate or the 2 gamma detectors in a dual-headed camera. Bilateral conventional craniocaudal and mediolateral oblique views are obtained that allow for direct correlation with mammography. For the Dilon Camera, the detector is on an articulating arm that can be rotated to obtain addition projections. With the Gamma Medica and GE Cameras, the detectors are on a gantry, similar to a mammography unit and additional images can be obtained by angling the gantry. The radiologist, in a manner comparable to diagnostic mammography, reviews the initial images. Additional images can be acquired as deemed necessary and may include exaggerated craniocaudal, true lateral, or in the case of a single detector camera, imaging with the detector on the opposite side of the breast. No additional radiotracer is administered when additional images are obtained. Imaging in projections comparable to mammography allows for multimodality correlative imaging. “Second-look” mammography is frequently utilized to identify MBI-detected lesions with subtle mammographic findings that might not have been appreciated before the MBI findings (Fig. 1). A complete MBI study consists of 4-12 images (significantly fewer than MRI), which allows for rapid interpretation and efficient workflow. In our experience, the time for interpretation of MBI is far less than that of MRI. With the current emphasis on workflow and efficiency, the markedly fewer images and shorter interpretation time allows for efficient as well as effective integration into clinical practice.
A.I. Huppe et al. While MRI is commonly utilized in many clinical scenarios, we find that approximately 15% of patients are unable to undergo evaluation by MRI due to implantable devices/ metallic foreign bodies, body habitus, renal insufficiency, patient positioning, and claustrophobia. Reticence to undergo MRI is a significant issue with the ACRIN 6666 trial demonstrating that 48% of women at substantially increased risk of breast cancer refused MRI, even when it was offered at no cost.16,17 Additional concerns with MRI include gadolinium accumulation in the brain, particularly with repeated studies. In our practice, it is critical to have MBI to offer to women who cannot or will not undergo MRI as an alternative physiologic imaging modality to detect cancers that are not visible with mammography or ultrasound. MBI has a high sensitivity, comparable to that of MRI, of 89%-96.4% (97% for invasive cancers and 93.8% for ductal carcinoma in situ [DCIS]).18-20 Of note, the sensitivity of MBI is independent of breast density, with sensitivities of 95.1% in dense breasts and 95.8% in nondense breasts.22,22 Not only can MBI detect cancer, but MBI can also detect high-risk lesions such as ADH and ALH.23 This can be of clinical importance especially as the risk of developing breast cancer in young women with ADH and in women with multiple foci of ADH has recently been shown to be as high as 50%.24 In this high-risk population, risk reduction strategies are often considered and may include chemoprevention. Therefore, the identification of ADH and other high-risk lesions is clinically important. MBI has many advantages, however, as with all imaging modalities, there are disadvantages. The disadvantages of MBI include the lack of anatomy included when compared to MRI and the radiation required for MBI. Initially, MBI was performed using 20-30 mCi (740-1100 megabecquerels [MBq]) of technetium sestamibi. Recently, a number of studies have demonstrated the use of 5-10 mCi, a 2.5-fold reduction in injected dose, with maintenance of sensitivity and specificity.19,20,25 The ability to utilize lower dose radiotracer has been demonstrated with both NaI detectors19 and CZI detectors.25 While both mammography and MBI incur radiation, the former involves exposure to the breast, while MBI is associated with whole-body radiation. A MBI examination using 8 mCi of technetium sestamibi has an estimated dose to the breast of 0.07 mGy/mCi,26 or approximately 0.53 mGy. However, the effective whole-body dose of MBI is approximately 0.325 mSv/ mCi, or 2.5 mSv for an administered activity of 8 mCi.26 In comparison, the effective dose from 2-view digital mammography is 0.5 mSv. Although the use of MBI for generalized screening is not recommended, its use for diagnostic evaluation, in patients with contraindications to MRI, in women with newly diagnosed breast cancer and in women with dense breast tissue is reasonable.27 It is important to note that the MBI dose is significantly lower than the annual exposure limit of 50 mSv set by the U.S. federal government for radiation workers, and comparable to that of other cancer screening modalities. The purpose of this chapter is to provide a comprehensive review of MBI to include current indications and limitations, imaging technique, diagnostic performance of MBI including
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Figure 1 (A) MBI performed in this patient with a known malignancy in the contralateral breast demonstrates a focus of abnormal uptake in the central right breast. (B) “Second-look mammography” demonstrates a corresponding asymmetry seen when the nipple is in profile. Stereotactic biopsy of the asymmetry yielded atypical ductal hyperplasia, which was upgraded to DCIS upon excision.
up-to-date research, comparison with other imaging modalities and technical aspects regarding implementation of MBI into a practice.
Clinical Use MBI has been used in clinical practice for over 15 years with over 300 manuscripts describing the clinical and technical aspects of the technology. The sensitivity of MBI ranges from 89%-96%18-20 comparable to MRI.28 Several studies have compared MBI and MRI and have found comparable sensitivity with higher specificity for MBI.29 Since the indications for MBI are similar to MRI, it is of note that the sensitivity of the 2 modalities are similar, with a possibly higher specificity for MBI.9 As the clinical indications for MBI are in large part comparable to those of MRI, it can be integrated into clinical practice in a similar fashion. Indications for MBI include evaluation for extent of disease or occult disease in women
with a known diagnosis of cancer, high-risk surveillance, equivocal mammographic/sonographic findings, clinically challenging situations such as direct silicone implants and response to neo-adjuvant chemotherapy (Fig. 2). Studies have demonstrated that MBI detects occult foci of cancer in approximately 9%-11% of women with newly diagnosed breast cancer,30,31 changes surgical management in about a quarter of women with newly diagnosed breast cancer,32 and has similar sensitivity to and possibly higher specificity than MRI in comparable clinical situations.9 In addition, MBI has the potential to overcome the limitations of mammography when evaluating for local tumor recurrence.33 While mammography is the first-line modality for monitoring women following breast conservation therapy, it can be limited by morphologic changes in the posttreatment breast. Although the data is currently preliminary, studies have indicated that MBI is not adversely affected by posttherapeutic changes of the breast, and is a suitable alternative to MRI in this setting.34,35 A notable indication for MBI is problem solving for indeterminate cases or challenging clinical situations including
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Figure 2 (A) MBI in a patient with a known cancer demonstrates large mass-like uptake in the left breast. (B) Follow-up MBI after neo-adjuvant chemotherapy demonstrates complete resolution of uptake in the left breast, consistent with favorable response.
cases that require additional evaluation following a complete mammographic and sonographic evaluation. Additionally, certain clinical situations, such as women with implants or direct silicone injections for augmentation, present a diagnostic challenge when imaged with mammography, ultrasound, and even MRI (Fig. 3). Finally, MBI can also be used in evaluation for primary breast cancer in women with metastases or metastatic axillary lymphadenopathy of unknown primary. While MRI is often used for the detection of occult malignancy, given the similar sensitivities for cancer detection, MBI is an important alternative when MRI is not an option. In women with newly diagnosed breast cancer, MBI detects additional foci of disease comparable to that reported for MRI. In one series, MBI demonstrated occult disease in the ipsilateral breast in 6% of women and in the contralateral breast in an additional 3% with a PPV of positive MBI findings of 35%.30 In a second series of 138 women with newly diagnosed breast cancer additional foci of disease were detected in 11% of women with a PPV of 60% for suspicious findings on MBI.31 In this population of women where detection of additional disease is critical and where the specificity is lower, the availability of direct gamma-guided biopsy is critical. In 218 women with newly diagnosed breast cancer thought to be
eligible for breast conserving therapy, MBI resulted in a change in management in 26% of patients.32 In this study, pathology of the mastectomy specimen confirmed that all of the women who were converted from breast conserving therapy to mastectomy due to MBI findings would have had residual disease had breast cancer therapy been performed. Studies evaluating the impact of pathologic subtypes of breast cancer on MBI sensitivity have demonstrated that both tumor size, grade, and pathologic subtype are important. In a series of 149 invasive breast cancers, the sensitivity of MBI was 98%. The cancers were stratified by size and pathologic grade. All invasive cancers measuring greater than 7 mm and all cancers grade 2 or 3, regardless of size (even those less than 5 mm) were positive. Of the grade 1 invasive cancers less than 7 mm, 50% were positive, demonstrating that MBI can detect virtually all clinically significant breast cancer and that grade and size are both factors in MBI detection of cancer.11 Invasive lobular carcinoma is often difficult to detect clinically as well as with traditional imaging with mammography and ultrasound. In a multi-institutional study, the sensitivity of MBI for detecting invasive lobular carcinoma was greater than mammography, ultrasound, or MRI.36 In this study, the sensitivity of MBI was 93% compared to MRI with a sensitivity of 83% for
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Figure 3 (A) Screening mammogram in a patient with a history of silicone injections demonstrates innumerable injection granulomas significantly limiting evaluation for malignancy. (B) MBI in this patient demonstrates no abnormal uptake. (Color version of figure is available online.)
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6 invasive lobular cancer. Similar findings were reported for the sensitivity of ILC in a series reporting the sensitivity of MBI by pathology subtype.37 Several studies have shown that MBI cannot reliably assess axillary involvement of breast cancer, although axillary uptake due to extravasation at the time of radiotracer injection is higher than in metastatic lymphadenopathy.38 Over 30 states now have density inform laws requiring women be told their breast density and some require information about adjunct imaging modalities available to detect mammographically occult cancers. The sensitivity of MBI is equal in women with dense and nondense breasts.21 Yet, the approach to supplemental screening in women with dense breasts varies. Ultrasound remains the primary modality for supplemental screening in women with dense breasts.39 Several recent studies have reported the use of MBI for supplemental screening in women with dense breasts. The rationale is that the cancer detection rate of 7-16 cancers per thousand women screened with MBI is substantially higher than the 2-7 cancers found with ultrasound.22,40 Screening with MBI also has lower recall rate of 6%-8% and a higher PPV3 of 33%.25 The issue of the additional radiation with MBI must be considered. Nevertheless, MBI is increasingly being used for adjunct screening in women with dense breast due to the more widespread use of lower dose of the radioisotope and the substantially higher cancer detection rate. Furthermore, screening with MBI results in an entire study consisting of 8 images, far fewer than the hundreds or thousands of images obtained with tomosynthesis, handheld or automated screening ultrasound, or MRI. MRI is indicated to screen women at greater than 20% lifetime risk of breast cancer.41 Studies have shown that in women at increased risk of breast cancer who cannot or will not undergo MRI can expect a similar rate of cancer detection using MBI42,43 (Fig. 4). In a comparative study of MRI and MBI in women at increased risk for breast cancer with dense breast tissue, the sensitivities of MRI and MBI were comparable, and the specificity of MBI was higher.29 Of note, the majority of incremental cancers detected with MBI screening are invasive cancers. Furthermore, in a study comparing the costs of screening, diagnostic work-up and biopsies, the cost per cancer detected with mammography and MBI was lower than mammography alone.44 Several studies have evaluated the use of MBI in evaluating both the presence and the extent of residual tumor in women undergoing neoadjuvant chemotherapy. In one study of 122 patients where MBI was compared to MRI, the assessment of residual tumor was equal in MBI and MRI. However, when assessment of extent of residual tumor was compared, both MRI and MBI underestimated the extent of residual tumor in luminal-type breast cancer, while MRI underestimated the extent of residual disease more than MBI in Her2 positive breast cancer. Both MBI and MRI generated accurate tumor sizes and extent of residual disease in triple negative breast cancer.45 A meta-analysis of 3 studies, which included 107 patients, evaluating MBI during neo-adjuvant chemotherapy reported a sensitivity of 87% and a specificity of 93%.46 Larger, multi-institutional studies are needed to further evaluate the
role of MBI in assessing the presence and extent of residual disease following neo-adjuvant chemotherapy. A negative MBI examination is clinically important. In the screening environment, whether it be in women with dense breasts or in high-risk women, the 98% negative predictive value is extremely reassuring.43 In women with newly diagnosed breast cancer, confirming only the known cancer with no other areas of abnormality is critically important in management decisions.
Imaging Technique MBI examinations are performed following an intravenous injection of technetium-99m sestamibi. No patient preparation is necessary. Some have suggested fasting for several hours before the examination and keeping the patient warm.22 However, we have not found that necessary. Tc-99m sestamibi, a radiopharmaceutical with a 140 Kev emitting gamma ray, was initially approved as a myocardial perfusion agent in 1991 and has since had a history of safe use with minimal adverse events; the only absolute contraindications are pregnancy and allergy to the radiotracer. The reported incidence of adverse effects is low (1-6 per 100,000). Although the initial dose of Tc-99m sestamibi was 20-30 mCi, we and others are using 5-10 mCi.19,25 Imaging begins immediately after radiotracer administration and continues for 175,000 counts which takes 5-10 minutes per image. The radiotracer is taken up by the breast almost immediately following injection, and the activity remains relatively constant for the duration of the study. A nuclear medicine technologist with training in breast imaging should perform the imaging or, alternatively, a nuclear medicine technologist can perform the injection with the imaging performed by a mammography technologist. Highresolution images are obtained while the breast is in gentle compression using conventional craniocaudal and mediolateral oblique mammographic positioning with careful attention to inclusion of the entirety of the breast. Similar to mammography, additional views can be obtained to completely evaluate the breast such as exaggerated craniocaudal, true lateral, and axillary tail views. The examination is performed with the patient comfortably seated and requires approximately 40-50 minutes. Patients undergoing MBI can listen to music or watch videos during the examination. Similar to MRI, when MBI is performed for surveillance in high-risk women or for follow-up of a previously visualized finding, it is optimal to perform the study during the follicular phase of the menstrual cycle, that is, days 7-14. This approach should minimize the background parenchymal radiotracer uptake, similar to background parenchymal enhancement with MRI. However, if there is a clinical indication, the examination can and should be performed anytime during the menstrual cycle. In women with newly diagnosed breast cancer, it is recommended that the injection be in the contralateral arm to avoid uptake in the axilla from extravasation and confound interpretation of axillary involvement.38 Radiologists experienced in breast imaging should perform interpretation of MBI examinations. As with most breast
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Figure 4 Screening mammogram in a high-risk patient demonstrates heterogeneously dense breast tissue. The parenchymal pattern was stable without mammographic evidence for malignancy. Subsequent imaging with MBI in this patient demonstrates mass-like uptake in the lower outer quadrant that yielded invasive lobular carcinoma upon tissue sampling.
imaging, multimodality correlation results in optimal interpretation. This may include “second-look mammography” where, based on MBI findings, the mammogram is reevaluated and subtle findings previously thought to be insignificant are now re-considered. Furthermore, in a study evaluating 173 cases of positive screening MBI examinations, correlation with clinical history or other imaging modalities resulted in confirmation of correlative benign findings in 31% of the cases.44 Interpretation of a positive MBI examination, whether performed for screening or diagnostic reasons, often
leads to directed ultrasound to identify the abnormality for biopsy (Fig. 5). Since the widespread use of breast MRI, breast imaging radiologists have become adept at correlating ultrasound findings with MRI, and can translate this ability to MBIidentified findings. In a study of 1585 women who underwent screening MBI, 3% went on to biopsy. Of those, 74% has the MBI-detected lesions recommended for biopsy were identified with directed ultrasound and 26% required MRI to target the suspect lesion.44 The use of MRI can be obviated by the availability of direct gamma-guided biopsy. This demonstrates
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Figure 5 (A) Molecular breast imaging in this patient with known right breast cancer demonstrates an abnormal focus of uptake in the medial left breast for which second-look ultrasound was recommended. (B) Second-look ultrasound demonstrates an irregularly shaped hypoechoic mass corresponding to the MBI finding. Biopsy yielded invasive ductal carcinoma. (Color version of figure is available online.)
that although the majority of lesions identified with MBI can be seen with directed ultrasound, direct gamma-guided biopsy is needed to optimally integrate MBI into clinical practice. A direct gamma-guided biopsy device for MBI-identified lesions has been FDA cleared for the Dilon Technologies camera (GammaLoc, Dilon Technologies) since 2009 and the GE Camera (GE, Discovery NM 750b) biopsy device recently received FDA clearance. With the availability of a direct gamma-guided biopsy device, optimal integration of MBI into clinical practice is possible. In a recent study of 104 gammaguided biopsies, all of which were successfully performed, 9 invasive cancers, 6 DCIS, and 17 high-risk lesions were found demonstrating a PPV of 30.8% for abnormal pathology
and 16.3% for cancer.47 These findings are similar to that reported for MRI-guided biopsy.48 A lexicon has been developed for MBI in order to improve and standardize MBI imaging reports.49 Components of the lexicon are similar to BIRADS whereby the technique, background enhancement, technical factors, and standardized lesion terminology are included. This has been shown to improve interobserver variability and accuracy. However, there are notable differences between BIRADS and the MBI lexicon in that BIRADS 3, probably benign, lesions identified with MBI imaging had a malignancy rate of 5%50 compared with the accepted 2% for mammography.51
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Implementation Into Practice MBI has become an integral component of our breast imaging practice. Without it, a substantial percentage of patients do not have the ability to obtain critically important physiologic imaging. MBI is not meant to replace other breast imaging modalities. Rather, it is an addition to our armamentarium of technology and modalities to allow for the diagnosis of early, curable breast cancer. It will not replace screening mammography, but as discussed above, contributes to the diagnosis of cancer in numerous clinical situations and in screening in women at increased risk and with dense breast tissue. Successful integration in a clinical practice requires that MBI be in the breast imaging area. When MBI is placed in nuclear medicine, the fragmentation from breast imaging makes it nearly impossible to seamlessly integrate into clinical practice. For some MBI imaging systems, such as the Dilon system, a dedicated room is not necessary since the device is approximately the size of an ultrasound unit and is portable. For others, which use a fixed gantry such as the Gamma Medica and GE systems, a dedicated room is necessary. There is no additional shielding that is needed for the room where the injections or the imaging occurs. Any facility using MBI must have access to a physicist who maintains a radioactive materials license, an appropriately licensed physician, a state-licensed nuclear technician for radiotracer injection and a radiation safety officer. For many tertiary care centers, these individuals are generally readily available, often already integrated into the radiology department. However, this may present more of a challenge for smaller, community-based practices with more limited resources. Several of the camera system vendors have a program for turn-key integration of nuclear medicine imaging of the breast in order to make integration of MBI into clinical practice easier. Practices must additionally consider the coverage by insurance and acceptance by referring clinicians, both of which will vary among communities. As with any new technology, familiarity by the referring physicians is critical for success. Presenting MBI at hospitalbased conferences can be extremely helpful as can identifying specific indications where MBI is advantageous. The Society of Nuclear Medicine has published clinical indications for MBI52 and the American College of Radiology has published appropriateness criteria for MBI. There is also an accreditation program by the ACR for MBI.53,54 More recently, the ACR has developed a teaching module for MBI interpretation with a no-cost online program of over 100 cases with quizzes and self-assessment, which physicians incorporating MBI into their clinical practice should consider reviewing.
Conclusion MBI is a valuable tool for both breast cancer screening and evaluation of breast cancer. It provides a means of physiologic imaging for a significant subset of women for whom MRI is not an option, while demonstrating similar sensitivities and improved specificities over MRI. It is a clinically important option for women who cannot undergo MRI, or for screening
9 women with dense breasts. Future directions include the development a newer radiotracers and further development of breast-specific gamma cameras, particularly with integrated correlative imaging with mammography and possibly MRI. Additionally, rigorous, multi-institutional studies evaluating MBI as well as comparing MBI to MRI are necessary, as are further additional cost analysis studies to further our understanding of the optimal use of this exciting emerging technology.
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